The long term goal of this project is to gain a more complete[unreadable] understanding of the role of ion transport pathways in the regulation[unreadable] of pulmonary and renal arterial tone. This renewal application is based[unreadable] upon several advances made during the previous funding period and[unreadable] focuses on characterization of the role of intracellular Ca2+ stores and[unreadable] selected sarcolemmal ion channels in excitation-contraction coupling of[unreadable] isolated pulmonary and renal arterial smooth muscle cells (PASMC and[unreadable] RASMC). A combination of experimental approaches will be utilized to[unreadable] obtain cellular and molecular information which will be related back to[unreadable] the physiology of intact pulmonary and renal arteries. We will[unreadable] specifically determine the physiological role, biophysical and[unreadable] pharmacological properties and the molecular identity of nonselective[unreadable] cation channels and volume-regulated chloride channels in these[unreadable] specialized vascular beds. We will also examine the properties of[unreadable] ryanodine- and inositol triphosphate (IP3)-sensitive Ca2+i stores in[unreadable] RASMC and PASMC and identify any physiologically relevant interactions[unreadable] which may occur between these two stores and possible effects of Ca2+[unreadable] released from these stores on sarcolemmal ion channels. Finally, we[unreadable] will test the hypotheses that alterations of Ca2+i stores, pHi,[unreadable] sarcolemmal K+, Ca2+ and/or CI- channels represent critical early events[unreadable] in the initiation of hypoxic pulmonary vasoconstriction. Despite the[unreadable] clinical relevance of these two vascular beds to a number of important[unreadable] disease processes, relatively little information is presently available[unreadable] on the role of ion channels and Ca2+i stores in the control of pulmonary[unreadable] and renal vascular tone. This study will help fill the existing gap of[unreadable] knowledge regarding the role of ion channels and Ca2+i stores in[unreadable] vascular reactivity of the renal and pulmonary circulation. The medical[unreadable] significance of this project is that the results obtained have[unreadable] significant potential of revealing new, important cellular mechanisms[unreadable] responsible for pulmonary and systemic hypertension and could lead to[unreadable] the development of new drugs and therapeutic strategies to treat or[unreadable] prevent these conditions.[unreadable]